Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

• the present invention is concerned with novel thiazole derivatives useful as neuropeptide Y (NPY) receptor ligands, particularly neuropeptide Y (NPY) antagonists.
• NPY neuropeptide Y
• NPY neuropeptide Y
• WO 99/62892 discloses thiazole formamide derivatives useful as NPY antagonists.
• WO 03/072577 and WO 2004/014884 both published after the present priority date, disclose thiazole derivatives also having utility as NPY antagonists.
• the invention is concerned especially with compounds of formula I and pharmaceutically acceptable salts and esters thereof wherein R 1 is amino, optionally substituted phenyl, naphthyl or optionally substituted heteroaryl; R 2 is hydrogen or alkyl; R 3 is hydrogen, alkyl or halogen; R 4 is alkyl or halogen; R 5 is hydrogen, alkyl or halogen; a is zero or 1; and b is zero, 1 or 2.
• Neuropetide Y is a 36 amino acid peptide that is widely distributed in the central and peripheral nervous systems. This peptide mediates a number of physiological effects through its various receptor subtypes. Studies in animals have shown that neuropeptide Y is a powerful stimulus of food intake, and it has been demonstrated that activation of neuropeptide Y Y5 receptors results in hyperphagia and decreased thermogenesis. Therefore compounds that antagonise neuropetide Y at the Y5 receptor subtype represent an approach to the treatment of eating disorders such as obesity and hyperphagia.
• NPY neuropeptide Y
• NPY neuropeptide Y
• Various receptors of neuropeptide Y (NPY) have been described to play a role in appetite control and weight gain. Interference with these receptors is likely to reduce appetite and consequently weight gain. Reduction and long-term maintenance of body weight can also have beneficial consequences on con associated risk factors such as arthritis, cardiovascular diseases, diabetes and renal failure.
• the compounds of formula I can be used in the prophylaxis or treatment of of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
• Objects of the present invention are the compounds of formula I and their aforementioned salts and esters per se and their use as therapeutically active substances, a process for the manufacture of the said compounds, pharmaceutical compositions, medicaments containing the said compounds, their pharmaceutically acceptable salts and esters, and the use of the said compounds, salts and esters for the production of medicaments for the treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
• alkyl signifies a straight-chain or branched-chain alkyl group with 1 to 8 carbon atoms, preferably a straight or branched-chain alkyl group with 1 to 6 carbon atoms and particularly preferred a straight or branched-chain alkyl group with 1 to 4 carbon atoms
• straight-chain and branched C 1 -C 8 alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, the isomeric pentyls, the isomeric hexyls, the isomeric heptyls and the isomeric octyls, preferably methyl and ethyl and most preferred methyl.
• cycloalkyl signifies a cycloalkyl ring with 3 to 8 carbon atoms and preferably a cycloalkyl ring with 3 to 6 carbon atoms.
• Examples of C 3 -C 8 cycloalkyl are cyclopropyl, methyl-cyclopropyl, dimethylcyclopropyl, cyclobutyl, methylcyclobutyl, cyclopentyl, methyl-cyclopentyl, cyclohexyl, methyl-cyclohexyl, dimethylcyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl.
• alkoxy signifies a group of the formula alkyl-O- in which the term “alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec. butoxy and tert.butoxy, preferably methoxy and ethoxy and most preferred methoxy.
• aryl signifies a phenyl or naphthyl group, preferably a phenyl group which optionally carries one or more substituents, preferably one to three, each independently selected from halogen, trifluoromethyl, trifluoromethoxy, amino, alkyl, alkoxy, alkylcarbonyl, cyano, carbamoyl, alkoxycarbamoyl, methylendioxy, carboxy, alkoxycarbonyl, aminocarbonyl, alkyaminocarbonyl, dialkylaminocarbonyl, hydroxy, nitro, alkyl-SO 2 -, amino-SO 2 -, cycloalkyl and the like.
• phenyl or naphthyl particularly phenyl optionally substituted with one to three, preferably one or two substituents independently selected from alkyl, halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl.
• heteroaryl signifies aromatic 5- to 10-membered heterocycle which comprises one or more, preferably one or two, particularly preferred one hetero atom selected from nitrogen, oxygen and sulfur, wherein nitrogen is preferred. It can be substituted on one or more carbon atoms by cyano, trifluoromethyl, trifluoromethoxy, alkyl-SO 2 -, amino-SO 2 -, halogen, alkoxy, hydroxy, amino, cycloalkyl, alkylcarbonyl, aminocarbonyl nitro, alkyl, and/or alkoxycarbonyl.
• Preferred heteroaryl cycles are thiophenyl or pyrrolidinyl, wherein thiophenyl and pyrrolidinyl are optionally substituted with one to three substituents, preferably one or two independently selected from alkyl, halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl.
• amino signifies a primary, secondary or tertiary amino group bonded via the nitrogen atom, with the secondary amino group carrying an alkyl or cycloalkyl substituent and the tertiary amino group carrying two similar or different alkyl or cycloalkyl substituents or the two nitrogen substitutents together forming a ring, such as, for example, -NH 2 , methylamino, ethylamino, dimethylamino, diethylamino, methyl-ethylamino, pyrrolidin-1-yl or piperidino etc., preferably primary amino, dimethylamino and diethylamino and particularly dimethylamino.
• halogen signifies fluorine, chlorine, bromine or iodine and preferably fluorine, chlorine or bromine.
• carbonyl alone or in combination signifies the -C(O)- group.
• nitro alone or in combination signifies the -NO 2 group.
• salts refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
• the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
• salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
• Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine resins and the like.
• the compound of formula I can also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula I are the hydrochloride salts.
• the compounds of formula I can also be solvated, e.g. hydrated.
• the solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration).
• pharmaceutically acceptable salts also includes physiologically acceptable solvates.
• “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters.
• lipase inhibitor refers to compounds which are capable of inhibiting the action of lipases, for example gastric and pancreatic lipases.
• lipases for example gastric and pancreatic lipases.
• orlistat and lipstatin as described in U.S. Patent No. 4,598,089 are potent inhibitor of lipases.
• Lipstatin is a natural product of microbial origin, and orlistat is the result of a hydrogenation of lipstatin.
• Other lipase inhibitors include a class of compound commonly referred to as panclicins. Panclicins are analogues of orlistat (Mutoh et al,1994).
• lipase inhibitor refers also to polymer bound lipase inhibitors for example described in International Patent Application WO99/34786 (Geltex Pharmaceuticals Inc. ). These polymers are characterized in that they have been substituted with one or more groups that inhibit lipases.
• lipase inhibitor also comprises pharmaceutically acceptable salts of these compounds.
• lipase inhibitor preferably refers to orlistat.
• Orlistat is a known compound useful for the control or prevention of obesity and hyperlipidemia. See, U.S. Patent No. 4,598,089, issued July 1,1986 , which also discloses processes for making orlistat and U.S. Patent No. 6,004,996 , which discloses appropriate pharmaceutical compositions. Further suitable pharmaceutical compositions are described for example in International Patent Applications WO 00/09122 and WO 00/09123 . Additional processes for the preparation of orlistat are disclosed in European Patent Applications Publication Nos. 185,359 , 189,577 , 443,449 , and 524,495 .
• Orlistat is preferably orally administered from 60 to 720 mg per day in divided doses two to three times per day. Preferred is wherein from 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitor is administered to a subject, preferably in divided doses two or, particularly, three times per day.
• the subject is preferably an obese or overweight human, i.e. a human with a body mass index of 25 or greater.
• the lipase inhibitor be administered within about one or two hours of ingestion of a meal containing fat.
• treatment be administered to a human who has a strong family history of obesity and has obtained a body mass index of 25 or greater.
• Orlistat can be administered to humans in conventional oral compositions, such as, tablets, coated tablets, hard and soft gelatin capsules, emulsions or suspensions.
• carriers which can be used for tablets, coated tablets, dragées and hard gelatin capsules are lactose, other sugars and sugar alcohols like sorbitol, mannitol, maltodextrin, or other fillers; surfactants like sodium lauryle sulfate, Brij 96, or Tween 80; disintegrants like sodium starch glycolate, maize starch or derivatives thereof; polymers like povidone, crospovidone; talc; stearic acid or its salts and the like.
• Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.
• the pharmaceutical preparations can contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants. They can also contain still other therapeutically valuable substances.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods known in the pharmaceutical art. Preferably, orlistat is administered according to the formulation shown in the Examples and in U.S. Patent No. 6,004,996 , respectively.
• the compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
• R 3 is hydrogen or alkyl, particularly hydrogen, methyl or ethyl. Particularly preferred are those compounds according to formula I, wherein R 3 is hydrogen.
• R 4 is alkyl, particularly methyl or ethyl. Particularly preferred are those, wherein R 4 is methyl.
• Another preferred object of the present invention are the compounds according to formula I, wherein a is zero. Further preferred are those compounds of formula I, wherein a is 1.
• R 1 is monoalkylamino, dialkylamino, phenyl, thiophenyl or pyrrolidinyl, wherein phenyl, thiophenyl and pyrrolidinyl are optionally substituted with one to three substituents independently selected from alkyl, halogen, alkoxy, trifluoromethoxy, nitro and trifluoromethyl.
• R 1 is thiophene-3-yl, 3-fluorophenyl, 4-fluorophenyl, 2-methylphenyl, 2-methoxy-5-methylphenyl, dimethylamino, thiophene-2-yl, 5-fluoro-2-methylphenyl, 2,4-difluorophenyl, 5-chloro-2-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chloro-5-trifluoromethylphenyl, 3-nitrophenyl, 4-nitrophenyl or 4-methoxyphenyl.
• the conversion of a compound of formula I into a pharmaceutically acceptable salt can be carried out by treatment of such a compound with an inorganic acid, for example a hydrohalic acid, such as, for example, hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc., or with an organic acid, such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
• an inorganic acid for example a hydrohalic acid, such as, for example, hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc.
• organic acid such as, for example, acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid or p-toluenesulfonic acid.
• the corresponding carboxylate salts can also be prepared
• the conversion of compounds of formula I into pharmaceutically acceptable esters or amides can be carried out e.g. by treatment of suited amino or hydroxyl groups present in the molecules with an carboxylic acid such as acetic acid, with a condensating reagent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or N,N-dicylohexylcarbodiimide (DCCI) to produce the carboxylic ester or carboxylic amide.
• an carboxylic acid such as acetic acid
• a condensating reagent such as benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or N,N-dicylohexylcarbodiimide (DCCI)
• a preferred process for the preparation of a compound of formula I comprises the reaction of a compound according to formula in the presence of a compound according to formula in order to obtain a compound of formula I, wherein R 1 to R 5 , a and b are defined as in claim 1.
• Particularly preferred is the above reaction, wherein the solvent is e.g. dichloromethane and / or MeOH in the presence or the absence of a base.
• Preferred bases are e.g. triethylamine and diisopropylethylamine.
• an object of the invention are compounds described above for the production of medicaments for the prophylaxis and therapy of illnesses which are caused by disorders associated with the NPY receptor, particularly for the production of medicaments for the prophylaxis and therapy of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
• compositions containing a compound of formula I described above and a therapeutically inert carrier.
• An object of the invention is also the use of the compounds described above for the production of medicaments, particularly for the treatment and prophylaxis of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
• a further object of the invention comprises compounds which are manufactured according to one of the described processes.
• a further preferred embodiment of the present invention is the use of a compound of the formula I in the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also receiving treatment with a lipase inhibitor, particularly preferred, wherein the lipase inhibitor is orlistat.
• an object of the invention are compounds described above for the production of medicaments for the prophylaxis and therapy of alcoholism.
• the full-length cDNA encoding the mouse NPY5 (mNPY5) receptor was amplified from mouse brain cDNA using specific primers, designed based on the published sequence, and Pfu DNA-Polymerase.
• the amplification product was subcloned into the mammalian expression vector pcDNA3 using Eco RI and XhoI restriction sites. Positive clones were sequenced and one clone, encoding the published sequence was selected for generation of stable cell clones.
• Human embryonic kidney 293 (HEK293) cells were transfected with 10 ⁇ g mNPY5 DNA using the lipofectamine reagent. Two days after transfection, geneticin selection (1 mg/ml) was initiated and several stable clones were isolated. One clone was further used for pharmacological characterization.
• HEK293 Human embryonic kidney 293 cells (HEK293), expressing recombinant mouse NPY5-receptor (mNPY5) were broken by three freeze/thawing cycles in hypotonic Tris buffer (5 mM, pH 7.4, 1 mM MgCI 2 ), homogenized and centrifuged at 72,000 x g for 15 min. The pellet was washed twice with 75 mM Tris buffer, pH 7.4, containing 25 mM MgCl 2 and 250 mM sucrose, 0.1 mM phenylmethylsulfonylfluoride and 0.1 mM 1,10-pheneanthrolin, resuspended in the same buffer and stored in aliquots at -80°C. Protein was determined according to the method of Lowry using bovine serum albumine (BSA) as a standard.
• BSA bovine serum albumine
• Radioligand competition binding assays were performed in 250 ⁇ l 25 mM Hepes buffer (pH 7.4, 2.5 mM CaCl 2 , 1 mM MgCl 2 , 1 % bovine serum albumine, and 0.01 % NaN 3 containing 5 ⁇ g protein, 100 pM [ 125 I]labelled peptide YY (PYY) and 10 ⁇ L DMSO containing increasing amounts of unlabelled test compounds. After incubation for 1 h at 22°C, bound and free ligand are separated by filtration over glass fibre filters. Non specific binding is assessed in the presence of 1 ⁇ M unlabelled PYY. Specific binding is defined as the difference between total binding and non specific binding. IC 50 values are defined as the concentration of antagonist that displaces 50 % of the binding of [ 125 I]labelled neuropeptide Y. It is determined by linear regression analysis after logit/log transformation of the binding data.
• the compounds of formula I and their pharmaceutically acceptable salts and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations).
• the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories).
• the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
• the compounds of formula I and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées and hard gelatin capsules.
• Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules.
• Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
• Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
• Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
• Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
• the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• the compounds of formula I and their pharmaceutically acceptable salts can be used for the prophylaxis and treatment of arthritis, cardiovascular diseases, diabetes, renal failure and particularly eating disorders and obesity.
• the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case.
• Examples 2 to 22 have been prepared according to the procedure described for the synthesis of Example 1 (see table 1).
• Examples 24 to 36 have been prepared according to the procedure described for the synthesis of Example 23 (see table 1).
• Examples 38 to 54 have been prepared according to the procedure described for the synthesis of Example 37 (see table 1).
• Examples 56 to 74 have been prepared according to the procedure described for the synthesis of Example 55 (see table 1).
• a compound of formula I can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg
• a compound of formula I can be used in a manner known per se as the active ingredient for the production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

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• 2004
  • 2004-08-04 MX MXPA06001570A patent/MXPA06001570A/es not_active Application Discontinuation
  • 2004-08-04 JP JP2006522949A patent/JP2007501823A/ja active Pending
  • 2004-08-04 DE DE602004010529T patent/DE602004010529T2/de active Active
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